Polymere Antitumormittel auf molekularer und zellulärer Basis?

Gros, Leo; Ringsdorf, Helmut; Schupp, H.

doi:10.1002/ange.19810930405

Cited by 110 publications

(30 citation statements)

References 190 publications

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“…One of the key issues which has been addressed in recent years regarding the pharmacological activity of macromolecular drug delivery systems is the significance of labile linker groups between the drug and the polymer ("Ringsdorf model"). [18,19] Therefore, in many macromolecular carrier systems the drug is linked to the polymer through a spacer molecule, which incorporates a predetermined breaking point that allows the bound drug to be released at a given cellular site. [7,19] Two types of linker molecules have been investigated: 1) acid-labile linkers, such as, hydrazones, [20,21] and 2) peptide linkers which can be cleaved by lysosomal enzymes.…”

Section: Methodsmentioning

confidence: 99%

Supramolecular Drug‐Delivery Systems Based on Polymeric Core–Shell Architectures

2003

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Hitting the target: Although the cellular uptake of supramolecular nanocarriers by endocytosis is not cell‐specific, a high passive selectivity has been observed in porous tissues, such as tumor tissue. The encapsulated, often toxic, drug is efficiently shielded and can develop its activity by selective release from the nanocarrier upon a shift of the pH value in the tumor tissue or inside the cell (see scheme).

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Section: Methodsmentioning

confidence: 99%

Supramolecular Drug‐Delivery Systems Based on Polymeric Core–Shell Architectures

2003

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“…antibodies, lectins) which is specific for the surface antigens of tumor cells are immobilised on the same dextran chain (plasma expander) will be the subject of further investigations [35,36].…”

Section: Discussionmentioning

confidence: 99%

Dextran-Linked Purine Nucleosides as Substrates and Inhibitors of Adenosine Deaminase

1982

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Dextran-bound adenosine, inosine, and nebularine have been prepared by carbodiimide coupling of their 2',3'-O-(4-carboxyethyl-l-methylbutylidene) cyclic acetal derivatives to 6-aminohexyldextran or 12-aminododecanyldextran. The latter polymers were prepared by cyanogen-bromide activation of dextran T80 followed by reaction with 1,6-diaminohexane or 1 ,12-diaminododecane. A high CNBr concentration leads to high-molecular-weight material, probably due to cross-linking, accompanied by a decrease in the digestion velocity using endo-dextranase from Penicillium species (EC 3.2.1.1 1).The dextran-bound nucleosides, as well as the nucleoside 2', 3'-O-(4-ethoxycarbonyI-l -methylbutylidene) acetal derivatives, were tested as substrates and inhibitors for adenosine deaminase. The K, of the adenosine acetal ester is identical to that of adenosine which shows that acetalation does not hinder complex formation. Since the maximum velocity of deamination is decreased fourfold, the modified substrate does not fit as well as the nucleoside. The polymer-bound acetals show a 3 -8-fold increase of K, or Ki and unchanged V compared to the corresponding acetals while dextranase digestion of the support does not alter the kinetic data. This indicates that the length of the polysaccharide chain does not interfere either with the complex formation or with the catalytic activity of the modified substrate. Since the activation energies of the deamination reactions of adenosine, its acetal ester, and dextran-linked adenosine are all similar (29.8 -32.3 kJ mol-') it is concluded that no diffusion control of the enzymatic reaction results from the binding of the nucleoside acetals to dextran T80.Heterogeneous enzyme-catalysed reactions can be divided into two categories: (a) reactions between soluble substrates and enzymes embedded in biological membranes or other native complex structures ; (b) reactions between a soluble enzyme and a polymer-bound or insoluble substrate [l -61.This prompted us to immobilise substrates and inhibitors of adenosine deaminase via cyclic acetal derivatives onto soluble dextran T80. Dextrans are a group of structurally related polysaccharides (mr, lo5 -10') elaborated by various microorganisms, especially by strains of Leuconostoc. All dextrans contain linear chains of 1 .+ 6-linked a-D-glucopyranose residues as the dominant structural feature [7]. Since we have already immobilised adenosine deaminase on dextran T80 [8], we now have a complete kinetic model system in which either the enzyme or its binding partners are covalently bound to a polymer matrix.The polymer attachment of nucleosides and nucleoside antimetabolites has several implications. (a) From the pharmacological point of view, the brief plasma persistance of small substrates and inhibitors can be overcome by linking the biomolecule to a polymer such as dextran T80, which is used as a blood volume expander. High activity of the modified substrate can only be expected if the position of attachment is carefully chosen and, if possible, a stereochemica...

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“…Means of drug delivery include target-specific biological carriers (Ghose et al, 1983) as well as other nonspecific microparticulate, macromolecular and synthetic carriers (Gregoriadis, 1981;Gros et al, 1981). Macromolecular drug carrier systems have been extensively developed in an attempt to modify the pharmacokinetic behaviour of antitumour drugs (Kaye, 1981).…”

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confidence: 99%

Poly-L-aspartic acid as a carrier for doxorubicin: A comparative in vivo study of free and polymer-bound drug

Pratesi¹,

Savi²,

Pezzoni³

et al. 1985

Br J Cancer

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Summary The synthetic polypeptide, poly-L-aspartic acid (PAA, mol. wt = 20,000) has been used as a macromolecular carrier for doxorubicin. The drug may be released in vivo through hydrolysis of the ester linkage formed between the carboxyl groups of the polymer and the drug side chain. PAA has been found to be a suitable carrier since it is a soluble, biodegradable, multivalent and nontoxic polymer. The toxicity and the therapeutic efficacy of free and polymer-linked doxorubicin have been evaluated in normal and tumourbearing mice, using a variety of experimental tumour systems. In studies on single and multiple drug administration, the results indicated that the polymeric derivative of doxorubicin had approximately 3-fold lower toxicity than did free drug. In addition, the severity of specific toxic effects, including cardio-and vesicant toxicity, were appreciably reduced following conjugation to PAA. The doxorubicin-PAA conjugate gave similar or rather greater therapeutic effects than free drug at less toxic doses. This effect, more evident in the highly sensitive tumours, suggests an improvement of the therapeutic index of the polymer-linked drug.

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Polymere Antitumormittel auf molekularer und zellulärer Basis?

Cited by 110 publications

References 190 publications

Supramolecular Drug‐Delivery Systems Based on Polymeric Core–Shell Architectures

Supramolecular Drug‐Delivery Systems Based on Polymeric Core–Shell Architectures

Dextran-Linked Purine Nucleosides as Substrates and Inhibitors of Adenosine Deaminase

Poly-L-aspartic acid as a carrier for doxorubicin: A comparative in vivo study of free and polymer-bound drug

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